This invention relates to a method of delivering therapeutic agents to the urethra, bladder and related structures and an urethral suppository for use in delivering therapeutic agents thereto.
In the treatment of various ailments affecting the urethra, bladder and related structures, it is generally not desirable to deliver therapeutic agents systemically. When delivery of such agents is accomplished in a systemic fashion such as, for example, orally or by way of a remote intravenous, intramuscular, subcutaneous or transdermal route, relatively high dosages are required in order to deliver an amount to the affected areas sufficient to have the desired therapeutic effect. The requirement for such relatively high dosages results from the dilution and dissipation effects attendant to such delivery methods as well as the loss of efficacy that can result from biochemical interactions between the therapeutic agent and unrelated systems. Further, due to the relatively high dosages required by systemic delivery methods, the risks of triggering both adverse reactions and unwanted side effects are increased. Accordingly, it is known to employ delivery methods which provide for the- local application of therapeutic agents in the treatment of urethral, bladder and related ailments in order to administer relatively small dosages to achieve delivery of relatively high concentrations of such agents to the affected areas.
While the local application of therapeutic agents permits the use of smaller dosages, and can avoid certain of the drawbacks associated with systemic delivery methods as mentioned herein above, a different set of problems arise with respect thereto. In the context of treating conditions affecting the urethra, bladder and related structures, for example, it is of primary importance that the local application of therapeutic agents be accomplished in a manner compatible with the anatomical structures involved. Accordingly, it is known to employ suppositories as delivery devices for therapeutic agents. Such suppositories are designed to be inserted into the urethra and to release therapeutic agents contained therein or applied thereon to the mucosal lining of the urethra. The release of therapeutic agents occurs upon liquefaction of the suppository which results from the transfer to the suppository of the body heat of the patient into whose urethra the suppository has been placed (Amemiya, T.; et. al. Development of emulsion type new vehicle for soft gelatin capsule. I. Selection of surfactants for development of new vehicle and its physical chemical properties. Chemical and Pharmaceutical Bulletin, 1998, Feb, 46(2): 309-13).
Various prior art suppositories, however, have been designed in such a manner that they are difficult to retain in position within the urethra where the precise delivery of therapeutic agents is desired. Experience has shown that such suppositories tend either to advance inwardly into the bladder or to be expelled out of the urethra prior to the complete decomposition within the urethra. In either case, the desired result of a precise placement of the specific dosage of the selected therapeutic agents within the urethra is not realized.
In order to address these shortcomings, it is known to configure urethral suppositories in the form disclosed in U.S. Pat. No. 5,085,650 to Giglio (the ""650 patent). The ""650 patent discloses an urethral suppository comprising a bulbous head and a conical tail joined by a narrow cylindrical shaft. As taught by the ""650 patent, upon insertion of the suppository into the urethra of a human female patient, the bulbous head thereof is advanced through the entire length of the urethra and penetrates into the bladder to anchor the suppository at the bladder neck. The conical tail of the suppository prevents the further advance of the suppository into the bladder. More specifically, once the suppository is positioned within the urethra, the portion of the bulbous head of the suppository which curves inwardly toward the shaft is designed to prevent the suppository from expulsion by its contact with the bladder walls at the bladder neck where the bladder narrows to the meet the proximal end of the urethra. At the same time, the flared portion of the conical tail, having an increasingly larger diameter than the shaft of the suppository as well as the urethra itself, is designed to prevent the suppository from over insertion by contact with the edges of the urethral orifice at the distal end thereof. It is through this combination of contact surfaces that the suppository disclosed in the ""650 patent is intended to be held in position during the liquefaction thereof
While suppositories configured with bulbous heads, conical tails and narrow cylindrical shafts, as disclosed in the ""650 patent aid in the placement and retention of suppositories within the urethra as compared with purely cylindrical suppositories that lack such features, such configurations permit, nonetheless, some slippage and, moreover. present certain other disadvantages. Because retention of the suppository is effected, in part, by the contact between the inwardly curved portion of the bulbous head with the bladder neck, it is required that the bulbous head of the suppository advance beyond the urethra and invade into the bladder itself. As a result, where therapeutic agents are infused throughout the material comprising the suppository, the portion of the dosage contained within the material comprising the bulbous head thereof is not positioned so that it is in direct physical contact with the mucosal lining of the urethra and thus is not absorbed readily therein. As a result, the precise delivery of a specific dosage through absorption by the urethra cannot be realized effectively. Further, insofar as the conical tail section of the suppository disclosed in the ""650 patent has a flat base, it is difficult to manipulate after insertion as it provides no projections which can be grasped readily. Moreover, the roundness of the conical tail renders the distal end of the suppository less than fully compatible with the anatomical structure of the labia. As a result, the comfort of the patient is compromised.
Any foreign body inserted into the urethra or bladder causes a degree of urgency, frequency, pain, and general discomfort to the patient. Medical devices, such as tubes, catheters, or instruments, commonly inserted in the bladder or urethra during urological procedures cause discomfort to patients (Duckett, J W; et. al. Intravesical morphine analgesia after bladder surgery. Journal of Urology, 1997, Apr 157(4): 1407-9;Campbell""s Urology. Edited by Walsh, P C; et. al. W. B. Saunders and Company, Six Edition, 1992). This discomfort can become extreme when the device contacts the sensitive tissue of the bladder neck. As an example, Foley catheters are used to provide bladder drainage after surgery when normal voiding is compromised. Foley catheters are tubes inserted through the urethra into the bladder. Inflation of a balloon at the catheter tip aids in the retention of the catheter in the bladder, but causes extreme discomfort to the patient as a result of contact between the balloon and the bladder neck. The patient feels urgency and a burning sensation that persists for a period of up to 24 hours. Typically, these patients are given local anesthetics such xylocaine to reduce the discomfort during this initial period.
The bladder neck is a highly vascularized and innervated tissue containing specialized cells that play an important role in the voiding cycle. The bladder is very sensitive to pressure. Any foreign body within the bladder neck will cause major discomfort to the patient. Various prior art suppositories have been designed which do not take into consideration the effect of contacting the bladder neck with a portion of the suppository. In addition, when portions of the suppository reside in different tissues such as the bladder neck and urethra, the dose of drug delivered by the suppository to an afflicted tissue cannot be readily determined. This is a result of different tissues causing the suppository to liquefy at different rates and having different rates of drug absorption.
The present invention relates to the provision of an improved method for delivering a therapeutic agent to the urethra and an easily manipulatable urethral suppository which is designed to overcome disadvantages associated with prior art suppositories.
Accordingly, an object of the present invention involves provision of a suppository shaped for cooperating with the action of the periurethral musculature to retain the suppository within the urethra with a minimum of pain and discomfort to the patient. Another object involves providing a suppository in which no portion of the suppository extends outside the urethra into the bladder, and does not make contact with the highly sensitive tissue of the bladder neck or urethral sphincter. A further object involves providing a one-size suppository which fits all patients regardless of their urethral length, and which remains stationary in the urethra regardless of body motion.
In accordance with one aspect of the present invention, there is provided a method for delivering a therapeutic agent to the urethra, bladder and related structures comprising the steps of providing a suppository comprising one or more therapeutic agents and a biocompatible carrier medium and shaped to be capable of cooperating with the action of the periurethral musculature and surrounding organs to retain the suppository within the urethra, inserting the suppository into the urethra, and retaining the suppository within the urethra by the action of the periurethral musculature for a period of time sufficient to permit the therapeutic agent to diffuse substantially into the urethra, in particular, the bladder and the vagina. The suppository utilized in the method of the present invention may be of any shape capable of being inserted into the human female urethra and of cooperating with the periurethral musculature in retaining the suppository within the urethra.
In accordance with another aspect of the present invention, there is provided an urethral suppository shaped to be capable of cooperating with the action of the periurethral musculature to retain the suppository within the urethra. Preferably, the suppository comprises a shaft having a rounded first end tapering along a longitudinal axis to a second end, and a substantially ellipsoidal knob extending from the second end of the shaft and sized to prevent insertion into the urethra, said shaft and knob comprising a composition of at least one therapeutic agent and a biocompatible carrier medium. More preferably, ellipsoidal knob of the suppository has a major axis which is substantially perpendicular to the longitudinal axis of the shaft. It is also preferred that the biocompatible carrier medium is capable of forming a relatively soft, pliable and smooth suppository so that the need for a lubricant to aid insertion can be eliminated and the risk of patient discomfort can be minimized.
The tapered shaft of the preferred suppository of the present invention provides a profile to the suppository which is particularly well suited to work in concert with the normal-action of the periurethral musculature, the urethral wall and surrounding organs found in human females. So configured, the naturally occurring pressure exerted by the periurethral musculature, the tissues of the urethral wall and surrounding organs is most advantageously utilized in retaining the suppository entirely within the urethra without contacting the tissue of the bladder. This retention permits the complete delivery of a precise dosage of one or more therapeutic agents to the mucosal lining of the urethra thereof without invasion into the bladder and which does not prevent the therapeutic agent within the liquified carrier agent from flowing into the bladder, vagina or related organs.